WR-2721: A UNIQUE CHEMOPROTECTIVE AND HYPOCALCEMIC AGEN

WR-2721是一种有机硫代磷酸酯化合物，在动物模型中 选择性地保护正常组织免受 放疗和烷化剂化疗的因子为1.2至4.0。 基于广泛的实验室研究，I/II期试验已经完成， 开始确定是否将WR-2/21与这些 治疗可以允许施用显著更高剂量的 化疗或放疗，导致更大的肿瘤细胞杀伤分数 具有降低宿主毒性的优点。 这项研究的目的是 项目是： 1)确定针对以下疾病的特定剂量调整因子： 环磷酰胺联合WR-2721预处理的骨髓毒性 对照临床试验。 目的是确定是否 高于已知耐受剂量的化疗剂量水平可以 以提高治疗率的方式施用。 2)确定保护的剂量调整因子， 顺铂诱导肾毒性与WR-2721预处理时，这些 药物以单剂量给药，伴随或不伴随甘露醇利尿， 以及每周或每日× 5剂量方案。 3)启动WR-2721的II期方案，并结合 环磷酰胺、顺铂和/或放疗，以确定 客观缓解率、缓解持续时间、生存期和毒性， 当这些抗肿瘤剂 使用WR-2721。 4)完成WR-2721的人体药代动力学数据，以确定最佳 WR-2721剂量、输注速率和放疗与放疗之间的间隔 化疗 5)确定WR-2721产生低钙血症的机制， 评价WR-2721作为降钙剂治疗高钙血症的疗效 与恶性肿瘤有关。 6)为了研究可能的机制， WR-2721和顺铂的协同作用。 以确定是否 WR-2721改变：a）游离和蛋白结合顺铂的药代动力学; B）顺铂排泄;和c）转运到正常和恶性肿瘤中 组织中

WR-2721 is an organic thiophosphate compound which in the animal model selectively protects normal tissues against the cytotoxicity of radiotherapy and alkylating agent chemotherapy by factors of 1.2 to 4.0. Based on extensive laboratory investigation, Phase I/II trials have been initiated to determine whether combining WR-2/21 with these antineoplastic therapies may permit administration of significantly higher doses of chemotherapy or radiation, leading to greater fractional tumor cell kill with the advantage of decreased host toxicity. The goals of this research project are to: 1) Determine the specific dose modification factors for protection against bone marrow toxicity from cyclophosphamide with WR-2721 pretreatment under controlled clinical trials. The objective is to determine whether chemotherapy dose levels above those known to be tolerated can be administered with improvement of the therapeutic ratio. 2) Determine the dose modification factors for protection against cis-platinum induced nephrotoxicity with WR-2721 pretreatment when these drugs are administered in single doses with or without mannitol diuresis, and in weekly or daily x 5 dosage schedules. 3) Initiated Phase II protocols of WR-2721 with combinations of cyclophosphamide, cis-platinum and/or radiotherapy to determine whether objective response rates, response duration, survival, and toxicity in a single tumor type are significantly affected when these anti-tumor agents are administered with WR-2721. 4) Complete human pharmacokinetic data on WR-2721 to define the optimal WR-2721 dose, rate of infusion, and interval between radiotherapy and chemotherapy. 5) To define the mechanism by which WR-2721 produces hypocalcemia and evaluate the efficacy of WR-2721 as a hypocalcemic agent in hypercalcemia asssociated with malignancy. 6) To investigate possible mechanisms contributing to the enhanced antineoplastic effects of WR-2721 and cis-platinum. To determine whether WR-2721 alters: a) free and protein bound cis-platinum pharmacokinetics; b) cis-platinum excretion; and c) transport into normal and malignant tissues.